Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for cancer development, other genetic and exogenous factors are also thought to be important. To investigate factors related to the etiology of NPC, two studies were conducted in Taiwan - a case-control study of approximately 1,000 individuals and a multiplex family study of approximately 3,000 individuals (350 families). To date, our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes, specific patterns of HLA and KIR genes, and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk; in contrast, formaldehyde exposure was not a significant risk factor. Exogenous risk factors identified within our family study were similar to those observed from our case-control study. Evaluation of gene expression profiles from nasopharynx tumor and normal cells suggest that genes involved in DNA repair and in the metabolism of nitrosamines are involved in NPC pathogenesis. Results from our tissue-based expression studies also suggest the possibility of loss-of-heterozygosity on the telomeric end of chromosome 14 in NPC, and that EBV gene expression within NPC tumor cells affect the expression of host genes involved in immune presentation. This suggests a possible mechanism by which EBV manages to evade immune surrveillance in NPC. Uaffected individuals from NPC multiplex families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To follow-up on this finding, we have evaluated the value of EBV serology to predict subsequent NPC risk among unaffected individuals from NPC multiplex families. We observed that individual with elevated antibody levels against several EBV markers are at a 4 to 6-fold increased risk of developing NPC within 10 years, but the low specificity of the antibodies evaluated suggest that improvements are required before such serology-based tests can be used clinically. Primary liver cancer, composed of two major histologic types, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the fifth most frequently occurring cancer in the world and the third most common cause of cancer mortality. Over 80% of liver cancers occur in Asia and sub-Saharan Africa, though incidence in low-rate areas, such as the U.S. and Europe, has been rising. Recently our research has focused on identifying factors associated with this increase in incidence. In record-linkage studies, we have found that hepatitis B virus, hepatitis C virus and diabetes are linked to the increasing incidence of HCC, while hepatitis C virus, human immunodeficiency virus, cirrhosis and diabetes are linked to the increasing incidence of ICC. We have also found that metabolic syndrome increases risk of both types of liver cancer. To follow-up on these findings, we are examining the contributions of these factors in 2 U.S. based research studies. We are also examining whether medications such as diabetes drugs, non-steroidal anti-inflammatory drugs and statins are related to the risk of liver cancer in developed countries. We have recently extended our interests in the etiology of breast cancer to also include a focus on rarely occurring male breast cancers. In an analysis within the large NIH-AARP cohort study, we identified that a family history of breast cancer in a female relative, obesity, physical inactivity and a history of bone fractures related to increased risk. An investigation within the U.S. Veterans Affairs computerized medical care system database found increased risksof male breast cancer associated with hospitalizations for Klinefelter syndrome, obesity, diabetes, gynecomastia, orchitis/epididymitis and cholelithiasis (latter only among African Americans). We are currently following up these findings in a pooled analysis in which are including data from the majority of case-control and cohort investigations. Cohort investigations will be particularly valuable towards assessing relationships with genetic markers and endogenous hormones. We are also hoping to obtain breast cancer tissue samples from some of the studies. Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at a risk of anal cancer that approaches the risk of cervical cancer for unscreened women living in developing countries. There is currently no accepted method for screening HIV-positive MSM for anal precancer to reduce the morbidity and mortality due to anal cancer; in the absence of a standard and effective screening modality, clinics often resort to anoscopy, a diagnostic procedure akin to colposcopy, and directed biopsies on all HIV-positive MSM. At Kaiser Permanente Northern California, we have enrolled about 400 HIV-positive MSM in a 2-year study to describe the natural history of HPV and evaluate the clinical utility of various tests to detect prevalent, 1-year cumulative, and 2-year cumulative anal precancer and cancer.ribe the natural history of HPV and evaluate the clinical utility of various tests to detect prevalent, 1-year cumulative, and 2-year cumulative anal precancer and cancer. clinical utility of various tests to detect prevalent, 1-year cumulative, and 2-year cumulative anal precancer and cancer.